- Alzheimer's disease (AD), lung
cancer (LC) and
glioblastoma (GBM, a brain cancer) continue to be major health concerns
globally and are associated
with increased mortality and morbidity.
- Alzheimer's disease is associated
with an increased risk of glioblastoma but a reduced risk of lung
- Current study suggests a possible
genetic basis to these varying associations and hopes to gain
insight into these conditions that may help spur newer and more effective
There may be a genetic connection to
explain the direct and inverse risk association between Alzheimer's disease
with glioblastoma and lung
according to a recent study published in Nature
Look Into Molecular Processes Underlying AD, GBM and LC
As stated earlier, Alzheimer's disease, lung
continue to pose major
health challenges worldwide to the healthcare community with not many effective
treatments currently available.
‘Genetic changes occurring in Alzheimer’s disease, glioblastoma and lung cancer, when analyzed in conjunction, throw up new insights and as yet unexplored treatment options for future research.’
Various reasons put forth for direct and
inverse comorbidities between diseases include environmental influences,
lifestyle or drug treatments.
The current research team believes that a
molecular basis might be able to explain these varying associations, at least
partly, and offer more information to fuel further research into developing
newer and better treatments.
Genes in these
Three Conditions and
To validate their hypotheses, the
research team embarked on a transcriptomic meta-analyses (an analysis that studies the combined data and statistics available from multiple studies) of these 3
In general, genes are said to be up-regulated
when their expression is increased from normal levels and down-regulated
when the expression is reduced. Both these situations are referred to as deregulation
(or disordered regulation)
interesting and most notable molecular observations were as follows.
AD and GBM
- A significant proportion of genes were
opposite directions (for example up-regulated
in AD but down-regulated
in LC) in Alzheimer's disease and lung cancer.
- Overall, 395 biological processes were
significantly deregulated in AD and/or LC. Among these 92 processes were
common to both diseases.
- Of the 92 common pathways, 21
processes were up-regulated in AD and down-regulated in LC, while 71 processes
in AD and up-regulated
- The pathways in which the genes were up-regulated in AD and
down-regulated in LC were those present in immune and inflammatory
- The genes that were down-regulated in AD and up-regulated
in LC included processes were related to synaptic transmission.
GBM and LC
- In contrast, a significant number of
genes were deregulated in the same direction in Alzheimer's disease (for example
in both conditions).
- Overall, more than 300 genes were
deregulated; not all were common to both.
- Of the deregulated genes, 8 genes
in both AD and GBM, and 14
in both conditions.
- The up-regulated genes were related to the
immune system function and the down-regulated ones were associated
with synaptic transmission.
- Interestingly, 10 genes that were
deregulated in opposite directions in AD and GBM, were also deregulated in lung
suggesting a possible molecular link to these 3 conditions.
AD, GBM and LC
- Among the 70 pathways found to be
up-regulated in GBM and the 177 processes up-regulated in LC, 43 were increased in both GBM and LC.
Most of these functions are related to the cell cycle, for instance
"DNA repair" or "mitosis".
- The 5 processes deregulated in
opposite directions between the two cancer types (GBM+/LC−) are related to
the immune function.
Reasons For Inverse Link Between AD And LC
- Overall, 198 genes were significantly
deregulated in the three diseases. Among these, 112 had a similar pattern
of deregulation in AD and GBM but demonstrated the opposite
pattern in LC.
- A comparison of the genes and
processes deregulated in AD, GBM and/or LC indicated "oxidative phosphorylation" to be down-regulated in AD and GBM,
and up-regulated in LC, pointing to potential metabolic differences
between these two types of cancer.
10 of the 11
processes down-regulated in AD and up-regulated in GBM were also
up-regulated in LC. The large majority of these were related to the cell cycle, a
central activity in tumorigenesis.
Genes down-regulated in AD but up-regulated in LC are those involved in
mitochondrial function. The following
mechanisms aim to explain how AD patients may have reduced LC risk
Possible Reasons For Direct Link Between AD and GBM
- In AD, oxidative phosphorylation is
dampened; it has been shown that oxidative phosphorylation is critical for
lung carcinoma growth.
- Decreased glutathione levels seen in
AD increases chemotherapy sensitivity in LC.
- Genes up-regulated in AD cause cell cycle
arrest and limit cell proliferation pathways involved in LC, reducing
lung cancer growth.
- Protein folding and proteasome
inhibition in AD decrease cell migration and cause cell death in LC.
- Diminished oxidative phosphorylation
in both conditions may play a role in their pathogenesis. Studies have
shown that methylene can be used to treat both AD and GBM.
- Persistent activation of immune
system may play a role in both diseases as well. Many studies have shown
an association between immune dysfunction and cancer as well as AD.
In conclusion, the study opens up possible
genetic factors linking AD, LC and GBM. Some of the insights gained in this
study may help in exploring newer
for these conditions, for example, combinations of proteasome and chaperone
inhibitors, oxidative phosphorylation or TCA cycle inhibitors and anti-oxidants
for LC treatment.